Dehydrated crystalline 6-(1-aminocyclo-alkylcarboxamido) penicillanic acids

ABSTRACT

THIS INVENTION IS CONCERNED WITH NEW AND NOVEL PARTIALLY DEHYDRATED AND ANHYDROUS 6-(1-AMINOCYCLOALKYLCARBOXAMIDO)PENICILLANIC ACIDS AND PROCESSES FOR THE PREPARATION THEREOF.

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Navman .anNT Hams( QLBuRa g n United States Patent O 3,553,201 DEHYDRATED CRYSTALLINE 6-(1-AMINOCYCLO- ALKYLCARBOXAMIDO) PENICILLANIC ACIDS Donald E. Clark, Norristown, Norman H. Grant, Wynnewood, and Harvey E. Alburn, Westchester, Pa., assignors to American Home Products Corporation, New York, N.Y., a corporation of Delaware Continuation-in-part of application Ser. No. 549,895, May 13, 1966. This application Oct. 3, 1967, Ser.

Int. Cl. C07d 99/16 U.S. Cl. 260-239.1 1 Claim ABSTRACT OF THE DISCLOSURE This invention is concerned with new and novel partially dehydrated and anhydrous 6(l-aminocycloalkylcarboxamido)penicillanic acids and processes for the preparation thereof.

DESCRIPTION OF THE INVENTION This is a continuation-in-part of U.S. Ser. No. 549,895, filed on May 13, 1966 and also entitled Dehydrated Crystalline 6 (l aminocycloalkylcarboxamido)Pencillanic Acids, and since abandoned.

This invention relates generally to the production of synthetic penicillins, and more particularly to novel partially dehydrated and anhydrous forms of certain 6 (1- aminocycloalkylcarboxamido)penicillanic acids defined hereinafter.

The fully hydrated forms of -(l-aminocycloalkylcarboxamido)penicillanic acids are already known to the art as described in United States Patent 3,194,802, wherein a simple and economical method for the production thereof is disclosed. By the terminology fully hydrated forms as used herein is specifically meant those crystalline forms which 4usually have at least one molecule of water bound chemically per molecule of the penicillin; e.g., at least the monohydrate thereof. It has been found, however, that 6(l-aminocyclobutanecarboxamido)penicillanic acid naturally exists as the hemihydrate.

Said 6-(laminocycloalkylcarboxamido) penicillin acids in the previously known forms are of recognized value for their broad spectrum antibacterial activity, and are useful as therapeutical agents in poultry and in mammals, and particularly, in man, in the treatment of infectious diseases caused by gram-positive and gram-negative bacteria, upon parenteral or oral administation. The compounds also have use as nutritional supplements in animal feed.

As disclosed in United States Patent 3,194,802, the compounds are generally prepared by reacting a suitable 4- substituted 2,5-oxazolidinedione (also known as an N- carboxy amino acid anhydride) with 6-aminopenicillanic acid. It is there disclosed that the reaction should take place in a cold aqueous solution, which is stirred for several hours at a temperature from just above the freezing point of the aqueous mixture to about 37 C. and preferably in the range of 0.l C.

The 6 (1 aminocycloalkylcarboxamido)penicillanic acids prepared by the foregoing procedure (and all other procedures as far as known) contain from about 3 percent to about 8 percent Water, as determined by the Karl Fischer method. This indicates that the compounds as prepared heretofore have been in the aforesaid form of their full hydrates; e.g., at least as the monohydrates thereof and the hemihydrate of -(l-aminocyclobutanecarboxarnido)penicillanic acid.

We have now made the surprising discovery that certain 6(l-aminocycloalkylcarboxamido)penicillanic acids may be prepared in previously unknown partially de- ICC The novel compounds of the invention are those embraced by the following general formula:

wherein n is an integer from 1 to 5 and m is a fraction from 1/2 to 0, with the proviso that when n is 1, mis less than 1/2.

These new compounds are characterized by the fact that they accordingly have very little, if any, water, up to no more than about 3.5 percent. Moreover, as new cornpounds, they have crystal structures differing in an essential Way from their known counterparts, as demonstrated by their differing infrared spectrographs, as appears in FIG. 1 9 of the drawings.

The 6 (l aminocycloalkylcarboxamido)penicillanic acids are further distinguished in that they have been found to have greater stability on storage. Because of their stability, coupled with their greater density, the efficiency of the production of the compounds in capsule dosage form is increased.

The foregoing differences and advantages of the novel compounds of the invention over those already known are of enhanced signicance, since the therapeutic effectiveness thereof is not at all sacrificed. On the contrary, the effectiveness of the partially dehydrated or anhydrous compounds of the invention is substantially equal to that of the kno-wn compounds on a Weight-by-weight basis. For example, when mice are challenged intraperitoneally with a penicillin-sensitive strain of S. aureus and a virulent strain of S. typ/wsa, and both the known types of compounds and those of the present invention are administered by the oral route to the separately infected mice, equal protection is lafforded by both types of compounds.

One of the new and novel methods for Ipreparing the novel compounds of this invention comprises heating the corresponding known fully hydrated compound in the presence of -free water at a temperature of from 40 C. to about C. until the new dehydrated compound is formed. The heating may best be carried out with the charge containing the fully hydrated compound and water at a pH of from about 3.0 to 7.0. Preferably, the free water is present in amount that is at least 50 percent by weight of the fully hydrated compound in the charge, and the heating is 'applied to the total charge under vacuum until the dry partially hydrated product is obtained. Advantageously, an organic solvent which is substantially fully miscible with water; e.g., ethanol, isopropanol, and the like, is added to the charge after the heating has been accomplished, but prior to drying. In another procedure, the required heat and water may be supplied by directly steaming crystals of the 4fully hydrated compound. It has been found more advantageous from the standpoint of feasibility `and economic processing to carry out the drying operation at a pH of from 5.0 to 5.5, at a temperature within the range of 60 70 C., and in the presence of at least 65 percent by volume of an organic solvent as defined hereinabove.

Another new and novel process for the preparation of the 6( 1-aminocyclohexanecarboxarnido)penicillanic acid of this invention comprises contacting the hydrated cornpound with a water, -miscible, dehydrating, organic solvent containing from about zero to about seventy-five percent of water, at a temperature range from about room temperature to reux temperatures for a period of about five to about thirty minutes. This latter process has the inherent advantage that it can be conducted at temperatures as low as room temperature thereby decreasing even further the possibility of hydrolytic destruction of 6-(1- aminocyclohexanecarboxamido)penicillanic acid which may occur at higher temperatures.

When the above-described dehydration is complete, the 6.-(1-arninocyclohexanecarboxamido)penicillanic acid of this invention is separated and dried by conventional procedures e.g., ltrated and vacuum dried.

Still another new and novel process for the preparation of the 6(1-aminocyclopentanecarboxamido)penicillanic acid of this invention comprises contacting the hydrated compound with Ia water-miscible, dehydrating, organic solvent containing from about zero to about seventy-five percent of Water at a temperature range from about 40 C. to about reflux temperatures for a period of about five to about thirty minutes. When the dehydration process is complete, the 6-(1-aminocyclopentanecarboxamido)penicillanic acid of this invention is separated and dried by standard procedures.

It has also been -found that iff the last above-described procedure for the preparation of the -(l-aminocyclopentanecarboxamido)penicillanic acid of this invention is conducted in the presence of a basic compound the dehydration may be conducted at te-mperatures as low `as about room temperature. Many such basic compounds will suggest themselves to those skilled in the art, for example, sodium acetate, sodium citrate, sodium tartrate, potassium lmaleate, potassium succinate, pyridine, aniline, sodium bicarbonate, potassium bicarbonate and ammonia. By the term water-miscible, dehydrating, organic solvent is meant such liquids as acetone, ethanol, isopropanol, npropanol, n-butanol, nitromethane, ethylene glycol, ethylene glycol monomethyl ether and dioxane, while other liquids of this type are readily known to those skilled in the art. As indicated above, it is advantageous to conduct these dehydration processes at lower temperatures so that hydrolytic decomposition is maintained at minimum levels. The above described processes have been successfully demonstrated to produce the partially hydrated and anhydrous penicillins of this invention. Alternatively, however, it has been proven that drying alone will not cause the desired transformation. Several lines of evidence were followed in such proof. Thus, it was found exceedingly difficult to lower the water content of a previously dried fully hydrated 6(l-aminocyclohexanecarboxarnido)penicillanic acid compound of the prior art below 2 percent by a variety of procedures, including Abderhalden drying at 55 C. with P205, azeotropic distillation with benzene, reaction with 2,2-dimethoxypropane and acid, the vacuum oven over P205 at 55 C., and treatment of dimethylformamide solution with Linde molecular sieve followed by dry ether crystallization. In all cases, the end product was still the already known hydrated compound. The foregoing is a further indication that one difference in kind between the known fully hydrated compounds and the partially hydrated or anhydrous compounds of the invention resides in the crystal formation.

However, once the dehydrated compounds of the invention are dissolved into water they are then apparently identical with the known compounds dissolved in Water and can be made to crystallize as the known hydrated form by the lower temperature, lesser water content crystallization procedures already known. No evidence has been found that the dehydrated compounds of the invention change to their corresponding hydrated form in the solid state. Further, the compounds of the invention are readily converted to form the known com-pounds by dissolving the former in water at any pH 'and c-rystallizing below 40 C., or freeze-drying.

4 The following examples are illustrative of the invention;

EXAMPLE I Anhydrate of 6(1-aminocyclopentanecarboxamido) penicillanic acid (A) A suspension consisting of 10.8 grams of 6-aminopenicillanic acid (6-APA), 6.3 grams of triethylamine, and 58 ml. of methylene dichloride is stirred at room temperature for one hour. It is then chilled to 0 C., and 4.1 grams of 1aminocyclopentanecarboxylic acid N-carboxyanhydride (cycloleucine NCA) is added. After one hour, an additional 4.1 grams of the NCA is added, and the mixture stirred for two hours, filtered, and 150 m1. of ethyl acetate is added to the filtrate. This solution is then concentrated to 60 ml., and 40 ml. of ethyl acetate, containing 4 grams of glacial acetic acid, is added. A precipitate forms, and on drying in vacuo over silica gel it weights 13.3 grams and contains 5.89 percent water.

(B) The anhydrate of the hydrated compound prepared in A above is formed as follows: 2 grams of hydrate is mixed with 2 ml. of Water and heated at 70 C. for two minutes; then 20` ml. of isopropanol is added and the system filtered. The residue (900 mg.) showed a markedly altered infrared pattern (cf. FIGS. 1 and 2 of the accompanying drawings), and possessed 0.1 percent water by the Karl Fischer assay.

EXAMPLE II Comparison of the anhydrate and the hydrate of 6-(1- aminocyclopentanecarboxamido)penicillanic acid Samples of the hydrate of 6-(l-aminocyclopentanecarboxamido)penicillanic acid (cycloleucylpenicillin hydrate) (3.8 percent water) obtained by the procedure of Example I(A), and anhydrate thereof (0.0 percent water) obtained by the procedure of Example I(B), are stored in closed containers for 17 hours at 78 C. The hydrate lost 35 percent of its ,B-lactam, while the anhydrate lost only 4 percent.

EXAMPLE III Anhydrate of 6(1aminocyclobutanecarboxamido) penicillanic acid Seven grams of the hydrate, which contained 3 percent water by Karl Fischer analysis, is heated with 5 ml. of water at C. for five minutes. Seventy ml. of isopropanol is then added, and the system filtered. The filter cake is washed with isopropanol, and the product dried.

Calcd. for C13H19N3O4 (percent): C, 49.8; H, 6.07; N, 13.5; S, 10.2. Found (percent): C, 49.6; H, 6.14; N, 13.6; S, 10.2.

The product possesses an infrared spectrum (FIG. 3 of the drawings) distinguished from that of the hydrate (FIG. 4 of the drawings) by the presence of characteristic absorption bands at the following frequencies (cm): 3450, 2100, 1690, 1640, 1530, 1220, 1180, 1030, 1000, 950, 875, 848, 805, 775 and 672.

After the solids are heated for 73 hours at 100 C., the hydrated penicillin lost percent of its essential IH-lactam, while the anhydrate lost none.

EXAMPLE IV Hydrate of 6(1-aminocyclohexanecarboxamido) penicillanic acid Two grams of the monohydrate of 6-(1-aminocyclohexanecarboxamido)penicillanic acid, obtained by a procedure similar to that of Example I(A), but substituting the suitable NCA, are dissolved in 2 ml. of water, and the solution is heated at 60 C. for four minutes. lPrecipitation occurs, 20 ml. of isopropanol are added, and the mixture is filtered. Thereafter, the filter cake is Washed with isopropanol, and the product dried.

Calcd. for C15H23N304S: 1/2 H2O (percent): C, 51.5;

H, 6.85; N, 12.0; H2O, 2.58. Found (percent): C, 51.3; H, 6.60; N, 12.0; H2O, 2.49.

The product possesses an infrared pattern (FIG. 5 of the drawings) which is distinguished from that of the monohydrate (FIG. 6 of the drawings) by the presence of characteristic absorption bands at the following frequencies (cmrl): 1670, 1510 and 765.

EXAMPLE V Hydrate of 6( 1-aminocyclohexanecarboxamido) penicillanic acid A charge of the monohydrate of 6-(1-arninocyclohexanecarboxamido)penicillanic acid weighing 8.6 g. is mixed with 7 ml. of water and heated at 60-65L7 C. for ve minutes. There is then added 80 ml. of isopropanol, and the system is filtered. After drying over phosphorus pentoxide under vacuum, the product possesses an infrared pattern (FIG. 5) distinguished from that of the monohydrate (FIG. 6) as described above. After being heated for 73 hours at 100 C., the solid penicillin retains all of its -lactam, according to hydroxamate assays.

EXAMPLE VI Hydrate of 6(1-aminocycloheptanecarboxarnido) penicillanic acid Seven grams of the dihydrate of -(l-aminocycloheptanecarboxa-mido) penicillanic acid obtained by the method of Example I(A), with the use of the suitable NCA, plus 5 ml. of water, are heated at 60 C., for live minutes. After addition of 70 ml. of isopropanol, the system is filtered, giving a product with an altered infrared pattern (cf. FIGS. 7 and 8) possessing sharp bands at 1110, 1070 and 791 cml.

EXAMPLE VII Hydrate of 6( 1-aminocycloheptanecarboxamido) penicillanic acid Eleven grams of the dihydrate of 6-(1-aminocycloheptanecarboxamido)penicillanic acid plus 7 ml. of water are heated at 5 5-5 8 C. for four minutes. Ihe viscosity of the system appears to increase suddenly, and a precipitate forms. The dried product gives the altered infrared pattern (FIG. 7) of the lower hydrate. IIn a stability test comprising heating for 73 hours at 100 C., the starting material lost 90 percent of its -lactam, in contrast to the loss of only 29 percent for the altered product.

EXAMPLE VIII Anhydrate of 6(1-aminocyclohexanecarboxamido) penicillanic acid (A) One gram of the monohydrate is mixed with 0.5 ml. of water and 0.5 ml. of isopropanol and then heated in a boiling water bath for three minutes. Another 8 ml. of isopropanol is added, the system brought to a boil, and then filtered. The insoluble component is the anhydrate having an infrared spectrograph (FIG. 9) distinct from that of the hemihydrate (FIG. 5) and of the monohydrate (FIG. 6).

`(B) One gram of the monohydrate is mixed with 0.2 m1. of water and 0.8 ml. of isopropanol and then heated in a 100 C. water bath for four minutes. Another 8 ml. of isopropanol is added, the system brought to a boil and then filtered. The insoluble component is the desired penicillin anhydrate having an infrared spectrograph as shown in FIG. 9.

(C) Two grams of the monohydrate are mixed with 0.6 ml. of H2O and 6 ml. of nitromethane. The system is heated to boiling and filtered. The insoluble component weighs 600 mg. and possesses a water content of 1 percent by Karl Fischer assay.

(D) Thirty-nine grams of monohydrate plus ml. of isopropanol plus 7.5 ml. of water are heated. At C. there is total solution. At 50 C. the solution 6 becomes more viscous, and a solid precipitates between 50 C. and 60 C. Isopropanol is added to a nal volume of 200 ml., the temperature is brought to 47 C., and the mixture is iiltered. The insoluble component possesses a water content of 1 percent (Karl Fischer), and has the infrared spectrograph of FIG. 9.

EXAMPLE IX Anhydrate of 6( 1-arninocyclopentanecarboxamido) penicillanic acid One gram of 6(1-aminocyclopentanecarboxamido) penicillanic acid monohydrate is suspended in 10 ml. of methanol and heated at 64 C. for five minutes. After cooling to room temperature, the insoluble crystals are separated and dried under vacuum to afford anhydrous 6( 1aminocyclopentanecarboxamido)penicillanic acid.

The above procedure is repeated with a seventy-tive percent methanol-twenty-ive percent water mixture `and a fifty percent methanol-fifty percent water mixture with similar results.

EXAMPLE X Anhydrate of 6(1-aminocyclopentanecarboxamido) penicillanic acid One gram of 6(1aminocyclopentauecarboxamido) penicillanic acid monohydrate is suspended in 10 ml. of ethanol and heated at 64 C. for tive minutes. After cooling to room temperature, the insoluble crystals are separated and dried under vacuum to afford anhydrous 6( 1-aminocyclopentanecarboxamido penicillanic acid.

Similarly, the same results are obtained when ethanol is replaced by isopropanol.

EXAMPLE XI Anhydrate of 6(1aminocyclohexanecarboxamido) penicillanic acid One gram of 6(1aminocyclohexanecarboxamido) penicillanic acid monohydrate is suspended in 10 ml. of methanol and kept at room temperature for thirty minutes. After cooling to room temperature, the insoluble crystals are separated and dried under vacuum to afford anhydrous 6 (1 aminocyclohexanecarboxamido)penicillanic acid.

i'In the same manner, anhydrous 6( l-aminocyclohexanecarboxamido)penicillanic acid is also obtained when the above procedure was conducted with a seventy-five percent methanol-twenty-ve percent water mixture and a fty percent methanol-fifty percent water mixture.

EXAMPLE XII Anhydrate of 6(1aminocyclohexanecarboxamido) penicillanic acid One gram of 6(l-aminocyclohexanecarboxamdo) penicillanic acid monohydrate is suspended in 10 ml. of ethanol and heated to reflux for five minutes. After cooling to room temperature, the insoluble crystals are separated and dried under vacuum to afford anhydrous 6( 1-aminocyclohexanecarboxamido) penicillanic acid.

Similarly, the same results are afforded when the above procedure is conducted in isopropanol.

EXAMPLE XIII Anhydrate of 6( l-aminocyclohexanecarboxamido) penicillanic acid Repeating the procedure of Example XII in acetone, there is also obtained 6(1-aminocyclohexanecarboxarnido) penicillanic acid.

EXAMPLE XIV Anhydrate of 6(1-aminocyclopentanecarboxamido) penicillanic acid A suspension of 350 grams of 6(1-aminocyclopentane carboxamido)penicillanic acid nionohydrate in 2.5 l. of methanol is boiled for ten minutes and then filtered. The insoluble penicillin, when dried under vacuum is the anhydrate form of 6(1-arninocyclopentanecarboxamido) penicillanic acid.

EXAMPLE XV Anhydrate of 6( 1aminocyclohexanecarboxamido) penicillanic acid To a suspension of 1000 g. of 6aminopenicillanic acid in liters of water, there is added with stirring 60 g. of sodium bicarbonate, followed by 261 g. of N-carboxy-laminocyclohexane carboxylic acid anhydride (NCA) and the mixture is stirred for ten minutes. Thereafter, there is added two additional batches of 261 g. of the NCA at ten minute intervals, and the mixture is stirred for thirty minutes after the final addition. The insoluble precipitate is suspended, ltered and Washed with 2.5 liters of water. The product is dried in an oven and the hydrated form of 6(1-aminocyclohexanecarboxamido)penicillanic acid is dissolved in absolute methanol to a twenty percent (Weight/volume) concentration. After thirty minutes, the crystals are removed by filtration to afford anhydrous 6 (1 aminocyclohexanecarboxamido)penicillanic acid.

EXAMPLE XVI Anhydrate of 6(1-aminocyclopentanecarboxamido) penicillanic acid To a suspension of 1000 g. of 6-APA and 61 g. of sodium bicarbonate in 2.9 liters of Water at room temperature, there is added 3-4 ml. of capryl alcohol as an anti-foaming agent. Three 240 g. aliquots of N-carboxyll-aminocyclopenanecarboxylic acid anhydride are added with vigorous stirring at half hour intervals. The mixture is stirred for two hours after the final addition, and is filtered, washed with 2 liters of water and dried in an oven. Conversion to anhydrous penicillin is carried out by heating a percent suspension in boiling methanol for ten minutes.

EXAMPLE XVII Anhydrate of 6(1-aminocyclopentanecarboxamido) penicillanic acid4 One gram of 6(l-aminocyclopentanecarboxamido) penicillanic acid monohydrate is suspended in 10 ml. of a fifty percent methanol-fifty percent Water mixture at 50 C. for five minutes. Thereafter, the insoluble crys- 8 tals are separated by filtration and dried to afford the title anhydrate.

Similar results are obtained when the above process is conducted at 37 C. for five minutes.

EXAMPLE XVIII Anhydrate of 6-( 1-aminocyclohexanecarboxamido) penicillanic acid One gram of 6 (1 aminocyclohexanecarboxamido) penicillanic acid monohydrate is suspended in ethanol at 64 C. for ten minutes. Thereafter, the insoluble crystals are filtered and dried under vacuum to afford the title anhydrate.

Similarlly, the above procedure is repeated in isopropanol.

EXAMPLE XIX Anhydrate of 6-(1-aminocyclopentanecarboxamide) penicillanic acid A suspension of 10 grams of -(l-arninocyclopentanecarboxamido)penicillanic acid, 5 grams of anhydrous sodium acetate and ml. of methanol are stirred for 30 minutes at room temperature and then filtered. The insoluble penicillin, when dried under vacuum, is the title anhydrate.

Similar results are obtained when the above process is repeated substituting one of the following basis compounds for sodium acetate: potassium acetate, sodium citrate, sodium tartrate, potassium maleate, potassium succinate, pyridine, aniline, sodium bicarbonate and potassium bicarbonate.

We claim:

1. The crystalline anhydrate of 6-(1-aminocyclohexanecarboxamido)penicillanic acid which is characterized by having an infrared spectrum as disclosed in FIG. 9 of the drawings, and possessing greater storage stability than hydrated crystalline 6(1-aminocyclohexanecarboxamido) penicillanic acid.

References Cited UNITED STATES PATENTS NICHOLAS S. RIZZO, Primary Examiner U.S. Cl. X.R. 424-271 

